The present invention relates to crystalline forms of 2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (Compound A) or a salt thereof, which are useful in the field of treatment of various cancers as a kinase inhibitor, especially as a Weel kinase inhibitor.
Cells have a checkpoint mechanism such that, when the DNA therein is damaged, then the cells temporarily stop the cell cycle and repair the damaged DNA (Cell Proliferation, Vol. 33, pp. 261-274). In about a half of human cancers, a cancer-suppressor gene, p53 is mutated or depleted and thereby the cells have lost the G1 checkpoint function thereof. However, such cancer cells still keep the G2 checkpoint function remaining therein, which is considered to be one factor of lowering the sensitivity of the cells to DNA-active anticancer agents and to radiations.
A Weel kinase is a tyrosine kinase that participates in the G2 checkpoint of a cell cycle. Weel phosphorylates Cdc2(Cdk1) tyrosine 15 that participates in the progress to the M stage from the G2 stage in a cell cycle, thereby inactivating Cdc2 and temporarily stopping the cell cycle at the G2 stage (The EMBO Journal, Vol. 12, pp. 75-85). Accordingly, in cancer cells having lost p53 function therein, it is considered that the G2 checkpoint function by Weel is important for repairing the damaged DNA so as to evade the cell death. Heretofore, it has been reported that the Weel expression reduction by RNA interference or the Weel inhibition by compounds may increase the sensitivity of cancer cells to adriamycin, X ray or gamma ray (Cancer Biology & Therapy, Vol. 3, pp. 305-313; Cancer Research, Vol. 61, pp. 8211-8217). From the above, it is considered that a Weel inhibitor may inhibit the G2 checkpoint function of p53-depleted cancer cells, thereby enhancing the sensitivity of the cells to DNA-active anticancer agents and to radiations.
Weel kinase inhibitors have been described in US Application 2005/0250836, WO2003/091255, Cancer Research, Vol. 61, pp. 8211-8217, or Bioorg & Med. Chem. Lett., Vol. 15, pp. 1931-1935. However, the compounds described in these references differ structurally from the compounds of the instant invention.
Compound A, its crystalline forms and salts thereof are described in International Publications WO2007/126128 (published on Nov. 8, 2007 to Merck & Co., Inc.), WO2007/126122 (published on Nov. 8, 2007 to Merck & Co., Inc.) and WO2008/133866 (published on Nov. 6, 2008, to Merck & Co., Inc.), which are hereby incorporated by reference in their entirety. Compound A has an excellent Weel kinase inhibitory effect and is useful in the treatment of cancer.